Keywords:

Abstract

Aim

We investigated the clinical efficacy and safety of switching to paliperidone (PAL) in elderly schizophrenia patients receiving risperidone.

Methods

The subjects were 27 inpatients who had been diagnosed with schizophrenia according to the DSM-IV. The patient's clinical symptoms were assessed using the Positive and Negative Syndrome Scale and the Clinical Global Impression-Severity of Illness Scale, and their safety was assessed using the Drug-induced Extrapyramidal Symptoms Scale, bodyweight, body mass index, and laboratory tests. We also investigated patient satisfaction using the Drug Attitude Inventory, a subjective outcome measure.

Results

No significant differences in clinical symptom improvement efficacy were seen between the PAL-switching group and the control group. The mean changes from baseline on the Drug-induced Extrapyramidal Symptoms Scale total score, Drug Attitude Inventory score, and prolactin level were significantly greater in the PAL-switching group than in the control group. Furthermore, patients with PAL needed less biperiden, even though they had similar risperidone-equivalent daily dosages to the control group.

Conclusions

The results of this study suggest that switching elderly patients from risperidone to PAL may result in superior safety and patient satisfaction, and may also make it possible to reduce the dosage of biperiden.

ELDERLY PATIENTS GENERALLY have reduced liver and kidney function, are more susceptible to adverse drug reactions, and are more likely to experience a reduction in their activities of daily living (ADL) and in their quality of life as a result of drug-induced adverse drug reactions. In elderly patients with schizophrenia, moreover, a decreased capacity for reality testing combined with a lack of insight make such patients more likely to lose their medication or make mistakes when taking their medication, resulting in severely inadequate treatment adherence. Therefore, when using drug therapy in elderly schizophrenia patients, it is important to ensure that the patients take their medication, to prevent adverse drug reactions as much as possible, and to keep the dosing regimen uncomplicated.

Against this background, paliperidone (PAL), the primary active metabolite of risperidone, which is a widely used drug treatment for schizophrenia, has been introduced into the clinical setting as a second-generation antipsychotic.[1, 2] It is thought that PAL is less likely to be affected by inter-individual differences in metabolism than risperidone, and to present less risk of drug–drug interactions.[3] The creation of an osmotic pump extended-release formulation that continually releases the drug at a constant rate over a period of 24 h, moreover, made it possible to maintain a stable plasma concentration,[4] and this made it possible to deliver an effective dose starting from the first dose. Symptom improvement efficacy was therefore obtained starting in the early stages of therapy, and the peak blood concentration was lower than those seen to date with oral risperidone. The risk of adverse drug reactions, such as extrapyramidal symptoms, is therefore lower.

In Japan, however, there are virtually no reports of PAL being administered to elderly patients with schizophrenia in order to study its efficacy and safety. In this study, we investigated the clinical efficacy and safety of switching to PAL in elderly patients with schizophrenia receiving risperidone.

Methods

Subjects

The subjects were 27 patients who were being treated on an inpatient basis at the psychiatry departments of Tanzawa Hospital and Seimo Hospital and had been diagnosed with schizophrenia according to the DSM-IV. Elderly schizophrenia patients (aged > 60 years) with persistence of symptoms and receiving risperidone monotherapy were enrolled into this study. Inclusion criteria were: (i) patients with schizophrenia according to the diagnostic criteria of the DSM-IV; and (ii) patients who had been treated with a stable dose of a risperidone monotherapy for at least 3 months. PAL is renally excreted. Patients with renal impairment were therefore excluded from this study. In addition, a group of patients (14 subjects) was established as a control group who continued receiving risperidone, and whose background characteristics were consistent with those of the patients in the group that were switched to PAL (13 subjects). The patients had received risperidone monotherapy before they were switched to PAL. The results were the same as for the control group.

Furthermore, all the subjects who participated in this study were inpatients whose treatment compliance had been confirmed each time by a nurse, and whose treatment compliance was thus assured. They were required to be symptomatically stable, as judged by the treating psychiatrist, to be able to complete all the clinical measures.

The study was a non-randomized, non-double-blind, open-labeled, flexible-dose, naturalistic observational trial of schizophrenia patients undergoing the usual care and who required a change in their medication because of persistent symptoms or troublesome side-effects. The reasons for shifting medication were lack of efficacy (n = 4) of previous medication or side-effect (n = 9). The risperidone group had persistent symptoms or side-effects. Patients had high scores in the Positive and Negative Syndrome Scale (PANSS), even though they were considered stable; however, these patients could not be considered refractory to antipsychotics.

This study was approved by the ethics committee of Tokai University Hospital. Only patients who had provided voluntary informed consent in writing to participate upon receiving a full explanation of the purpose and method of the study were enrolled, while patient confidentiality was afforded all due consideration, as were ethical considerations.

Switching method

Treatment was initiated within a dosage range of PAL 3–6 mg/day, depending on the dosage of the patient's previous therapeutic medication. Starting from the first dose of PAL, the dosage of the previous therapeutic medication was reduced, or totally stopped (until week 1), and an optimal treatment dosage was achieved within 2 weeks. As a guideline to risperidone and PAL equivalent dosages, we referred to the report of Arakawa et al. on brain D2 receptor occupancy ED50 values.[5]

Assessment methods

The following clinical assessments were performed both at baseline and at 12 weeks by the psychiatrist who was providing the actual therapy. Therefore, the evaluator was not blind to the patient's treatment. There were no reliability tests for those who were subjected to the PANSS,[6] the Clinical Global Impression-Severity of Illness Scale (CGI-S),[7] and the Drug-induced Extrapyramidal Symptoms Scale (DIEPSS);[8, 9] however, assessor training was provided to ensure a certain degree of reliability. The PANSS score change was the primary efficacy outcome. The percentage of responders (patients with improvements of at least 20% on the PANSS total score) and the CGI-S score change were the secondary efficacy outcome. Meanwhile, the DIEPSS, bodyweight, body mass index (BMI), and laboratory tests (total cholesterol, triglycerides, prolactin) were used to investigate safety. We also investigated patient satisfaction using the Drug Attitude Inventory (DAI-10),[10] a measure used to assess patients' attitudes towards drugs.

Statistical analysis

We used Fisher's exact tests for categorical variables and anova for continuous variables to make a direct comparison of the baseline demographic and the change in each assessment score between the PAL-switching group and the control group and to make a comparison of each assessment score before and after switching to PAL. Patients who continued receiving risperidone were analyzed using the paired t-test. If the data did not show a normal distribution, then Wilcoxon's signed rank sum test was used instead. The significance level was P < 0.05 in all analyses.

Results

No significant differences were seen between the PAL-switching group and the control group in the baseline PANSS total score, the baseline CGI-S score, the baseline DIEPSS total score, the baseline bodyweight, BMI, any of the laboratory tests, the mean daily dose of the previous treatment drug, the mean age at onset, the mean duration of illness, or the mean age of the patients (Table 1). None of the patients dropped out because of worsening psychiatric symptoms, serious adverse events, withdrawal of consent, or worsening adherence.

The PANSS total score and the PANSS subscales decreased significantly from baseline in both the PAL-switching group and the control group, but no significant differences were seen between the two groups (Table 2). There was no significant difference between the PAL-switching group (15.4%) and the control group (21.4%) in the percentage of responders. On the other hand, the mean change from baseline in the CGI-S score was higher in the PAL-switching group than in the control group, although the difference was not statistically significant.

The mean change from baseline on the DIEPSS total score was significantly greater in the PAL-switching group than in the control group (Table 2).

The mean changes from baseline on the bodyweight (kg) and BMI (kg/m2) were hardly changed in both the PAL-switching group and control group (Table 2). The total cholesterol (mg/dl) level decreased from baseline in both the PAL-switching group and the control group, but no significant differences were seen between the two groups (Table 2). On the other hand, the mean changes from baseline on the triglycerides level (mg/dl) was hardly changed in both the PAL-switching group and control group. The mean changes from baseline on the prolactin level (mg/ml) was significantly greater in the elderly group switched to PAL than in the control group. The most common adverse events were insomnia, anxiety, agitation, somnolence and headache (Table 3). Most adverse events were rated mild or moderate. Furthermore, in this study, no serious adverse events, such as suicide attempt, neuroleptic malignant syndrome, or tardive dyskinesia, occurred.

Table 3. Adverse events

Number (%) of patients

Control group (n = 14)

PAL-switching group (n = 13)

PAL, paliperidone.

Insomnia

3 (21.4)

2 (15.4)

Anxiety

2 (14.3)

1 (7.7)

Agitation

2 (14.3)

1 (7.7)

Somnolence

2 (14.3)

1 (7.7)

Headache

2 (14.3)

1 (7.7)

The mean change from baseline on the DAI-10 score was significantly greater in the PAL-switching group than in the control group (Table 4).

The average medication doses of both groups were 6.2 ± 4.0 (mg/day) with PAL in the switching group and 4.4 ± 2.0 (mg/day) with risperidone in the control group. No significant difference was observed in the mean change from baseline in the risperidone dose in the control group.

The biperiden dose in the PAL group was lower, but the mean change was greater in the PAL-switching group than in the control group (Table 4).

Discussion

No differences were seen in efficacy in the improvement of clinical symptoms between the PAL-switching group and the control group when inpatients with elderly schizophrenia were given PAL for 12 weeks, and the efficacy thereof with respect to clinical symptoms was comparable with that obtained in the control group, which continued to receive risperidone. Our findings are therefore consistent with the results of the clinical studies that have been conducted to date.[11]

The results suggested that switching from risperidone to PAL prevented the emergence of drug-induced extrapyramidal symptoms, which is normally one of the risk factors for reduced ADL in the elderly, compared to a control group that was continued on risperidone. These findings are consistent with those of previously conducted research.[12]

In schizophrenia patients, who are frequently obese, over time, weight gain increases the risk of cardiovascular lesions, and is a factor that can contribute to a worse vital prognosis, and has therefore become an issue of particular concern.[13, 14] Our findings showed that switching from risperidone to PAL resulted in virtually non-significant change in bodyweight, and that the BMI remained below 23, the level for normal bodyweight, suggesting that the risk of weight gain with PAL-switching is not high, and these results are also consistent with those of previously conducted research.[15] Switching from risperidone to PAL resulted in similar (though not significant) reductions in total cholesterol, which is a risk factor for cardiovascular disease. In patients switched from risperidone to PAL, neutral lipids remained in a normal range, virtually unchanged, which are an independent risk factor for coronary artery disease. The results of this study therefore show that, switching from risperidone to PAL resulted in a small effect on the lipid metabolizing system; however, one issue with PAL that has been reported is that it increases prolactin levels to the same extent as risperidone.[16] Over the long term, elevated blood prolactin levels place patients at risk for developing bone metabolism disorders and breast cancer. In this study, prolactin level increased in the control group and decreased in the PAL-switching group. Thus, the effect was not the same in the two groups. No clinical effects on sexual function were found. PAL may be better in regards to prolactin problems.

In an earlier study, it was reported that psychiatric symptoms, the oral palatability of antipsychotic medications, and extrapyramidal symptoms are factors affecting patient quality of life.[17] It has also been noted that maintaining good treatment adherence lowers a patient's risk of symptom recurrence.[18-20] Therefore, this suggests that PAL, the superior efficacy and safety of which improved patient satisfaction, may improve treatment adherence, and thereby contribute to symptom stabilization.

As elderly patients generally have reduced liver and kidney function and are thus more susceptible to adverse drug reactions, every effort must be made to reduce the dosing levels that are used in the elderly. Particularly in elderly patients, biperiden is known to impair cognitive function, and elderly patients being given biperiden must be watched carefully for signs of delirium. The results of this study showed that switching elderly patients from risperidone to PAL prevents extrapyramidal symptoms, which are risk factors for reduced ADL, compared to a control group continued on risperidone, suggesting that it may be possible to reduce the equivalent doses of biperiden.

Limitations

This study had a relatively small sample size, was a short-term study (12 weeks), and was furthermore an open-label, not a double-blind, study, so the possibility that bias was introduced to the results cannot be ruled out, and there are consequently limits to the conclusions that can be drawn from this study. A double-blind, randomized, controlled study in elderly subjects may be necessary in the future in order to clarify the efficacy and safety of PAL.

Conclusion

The results of this study suggest that switching elderly patients from oral risperidone to PAL may result in superior safety and patient satisfaction, and may also make it possible to reduce the dosage of biperiden.

Acknowledgment

Dr Matsumoto has received grant support from Yoshitomiyakuhin, GlaxoSmithKline, Dainippon Sumitomo, Pfizer, Meiji Seika, Janssen, Mitsubishi Tanabe, and Otsuka as well as honoraria from Lilly, Novartis, Yoshitomiyakuhin, GlaxoSmithKline, Dainippon Sumitomo, Pfizer, Meiji Seika, Otsuka, and Janssen. Dr K. Mikami has received a grant to participate in a national meeting from Tokai University School of Medicine. Dr Suzuki has received payment from Janssen, Otsuka, and Dainippon Sumitomo for lectures. Dr Gen received payment from Janssen for a lecture. Dr Inoue received payment from Eisai for a lecture. Dr Hibino has received payment from Janssen, Lilly, Otsuka, and GlaxoSmithKline for lectures. Dr Matsumoto has received payment from Janssen, Lilly, Astellas, Otsuka, and Yoshitomiyakuhin for lectures. Dr K. Mikami has received payment from Janssen, Otsuka, Astellas, Shionogi, and Yoshitomiyakuhin for lectures. Dr Otomo and Dr A. Mikami have no conflicts of interest.